This application addresses the broad Challenge Area (03) Biomarker Discovery and Validation and specific Challenge topic, 03-MH-101: Biomarkers in Mental Disorders and is entitled: Biomarkers of Suicide Risk in Adolescents and Young Adults: Factors that Contribute to High Risk in Bipolar Disorder. The proposed study addresses a critical gap in knowledge that could have a major impact on progress in suicide prevention: identification of neural circuitry biomarkers of adolescent and young adult suicidality and the biological and environmental factors that contribute to their development. Each year, over one million individuals lose their lives to suicide worldwide, including more than 32,000 Americans. For adolescents and young adults, suicide is the 3rd leading cause of mortality. Suicide is preventable. The critical issues in its prevention are its early identification and addressing its risk factors;however, biomarkers for adolescent and young adult suicidality have not been identified. The development of biomarkers of suicide in adolescents and young adults is especially critical, as it could contribute not only to prevention of suicide in this age group, but evidence suggests that antecedents to suicide through adulthood are present in childhood and adolescence during which biological and environmental factors alter the development of neural circuitry leading to lifelong increases in suicide vulnerability. The proposed study brings together a new multidisciplinary team of investigators to focus on the identification of neural circuitry biomarkers of adolescent and young adult suicidality. This includes investigators with expertise that spans basic molecular neuroscience, genetic, development, child and adult psychiatry, neuropsychology and neuroimaging study. Adolescents and young adults with bipolar disorder (BD) with a history of suicide attempts will be compared to adolescents and young adults with BD without a history of suicide attempts, as well as adolescents and young adults who do not have a psychiatric disorder. Suicidality in BD will be the focus of this project, initiating this new program of research in adolescent/young adult suicide, as BD is associated with one of the highest rates of suicide from amongst psychiatric disorders and is associated with a high rate of suicide in adolescents and young adults. Thus, study of development of suicide in BD could lead to the development of biomarkers associated with high risk for suicide and aid the development of prevention strategies that could be targeted to this high-risk group. The adolescents and young adults participating in this study will complete comprehensive assessments of psychiatric diagnosis, illness course features and symptoms, cognitive testing, and multi-modality magnetic resonance imaging brain scanning including functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI). Preliminary findings of the research team implicate the brain circuitry of emotion and impulse regulation. This brain circuitry will be investigated intensively using state-of-the-art brain scanning image analysis methods. Study of specific genetic variations will be performed and comprehensive information regarding psychosocial and environmental factors, including history of early stress and substance abuse, will be collected in order to study genetic and environmental factors that might influence risk for suicide. This project will initiate this program of research focused on identifying the causes and biomarkers for adolescent and young adult suicide. Long-term goals for this program include the development of new methods for early detection of risk for suicide and effective prevention methods. Relevance: Each year, over one million individuals lose their lives to suicide worldwide, including more than 32,000 Americans, and suicide is the 3rd leading cause of death in adolescents and young adults. It is preventable;however, in order to detect who is at risk and to develop effective prevention methods, identification of the brain circuitry biomarkers of suicidality in youth and the factors that contribute to the development of this circuitry are needed. This study would be one of the first investigations to utilize a comprehensive and intensive approach to elucidate brain circuitry biomarkers for suicide among adolescents and young adults and to study their genetic and environmental causes in a disorder associated with one of the highest risks for suicide among youths, bipolar disorder. PUBLIC HEALTH RELEVANCE: Each year, over one million individuals lose their lives to suicide worldwide, including more than 32,000 Americans, and suicide is the 3rd leading cause of death in adolescents and young adults. It is preventable;however, in order to detect who is at risk and to develop effective prevention methods, identification of the brain circuitry biomarkers of suicidality in youth and the factors that contribute to the development of this circuitry are needed. This study would be one of the first investigations to utilize a comprehensive and intensive approach to elucidate brain circuitry biomarkers for suicide among adolescents and young adults and to study their genetic and environmental causes in a disorder associated with one of the highest risks for suicide among youths, bipolar disorder.